The present invention generally relates to an apparatus and methods for determining absolute values of various properties of a physiological medium. In particular, the present invention relates to non-invasive optical systems and methods for determining absolute values of concentrations of oxygenated and deoxygenated hemoglobins (and/or their ratios) in the physiological medium. The present invention also relates to apparatus and methods for obtaining such absolute values by solving a generalized photon diffusion equation as well as its variations such as a modified Beer-Lambert equation.
Near-infrared spectroscopy has been used for non-invasive measurement of various physiological properties in animal and human subjects. The basic principle underlying the near-infrared spectroscopy is that physiological tissues include various highly-scattering chromophores to the near-infrared waves with relatively low absorption. Many substances in a medium may interact or interfere with the near-infrared light waves propagating therethrough. Human tissues, e.g., include numerous chromophores such as oxygenated hemoglobin, deoxygenated hemoglobin, water, lipid, and cytochrome, where the hemoglobins are the dominant chromophores in the spectrum range of 700 nm to 900 nm. Accordingly, the near-infrared spectroscope has been applied to measure oxygen levels in the physiological medium such as tissue hemoglobin oxygen saturation and total hemoglobin concentrations.
Various techniques have been developed for the near-infrared spectroscopy, e.g., time-resolved spectroscopy (TRS), phase modulation spectroscopy (PMS), and continuous wave spectroscopy (CWS). In a homogeneous and semi-infinite model, both of TRS and PMS have been used to obtain spectra of an absorption coefficient and reduced scattering coefficient of the physiological medium by solving a photon diffusion equation, and to calculate concentrations of oxygenated and deoxygenated hemoglobins as well as tissue oxygen saturation. CWS has generally been designed to solve a modified Beer-Lambert equation and to measure changes in the concentrations of oxygenated and deoxygenated hemoglobins.
Despite their capability of providing the hemoglobin concentrations as well as the oxygen saturation, one major drawback of TRS and PMS is that the equipment is bulky and expensive. CWS may be manufactured at a lower cost but limited in its utility because it cannot compute the oxygen saturation from the changes in the concentrations of oxygenated and deoxygenated hemoglobins. Accordingly, there is a need for novel CWS systems and methods thereof for measuring absolute value of concentrations of the hemoglobins as well as the oxygen saturation in the physiological medium.
The present invention generally relates to an apparatus and method for obtaining absolute values of concentrations of chromophores of a medium and/or absolute values of their ratios. More particularly, the present invention relates to non-invasive optical systems and methods for determining absolute values of oxygenated and/or deoxygenated hemoglobins in a physiological medium.
In general, wave propagation or photon migration in a medium is described by a generalized diffusion equation:                     I        =                  α          ·          β          ·          γ          ·                      I            0                    ·                      ⅇ                          {                                                                    -                    B                                    ·                  L                  ·                  δ                  ·                                                            Σ                      i                                        ⁡                                          (                                                                        ϵ                          i                                                ⁢                                                  C                          i                                                                    )                                                                      +                σ                            }                                                          (        1        )            
where xe2x80x9cIoxe2x80x9d is a variable representing an intensity of electromagnetic waves irradiated by a wave source and xe2x80x9cIxe2x80x9d is a variable for an intensity of electromagnetic waves detected by a wave detector. Parameter xe2x80x9cxcex1xe2x80x9d is generally associated with the wave source and/or medium and accounts for, e.g., characteristics of the wave source such as power and configuration thereof, mode of optical coupling between the wave source and medium, and/or coupling loss therebetween. Parameter xe2x80x9cxcex2xe2x80x9d is generally associated with the wave detector and/or medium and accounts for, e.g., characteristics of the wave detector, optical coupling mode between the wave detector and medium, and the associated coupling loss. Parameters xe2x80x9cxcex1xe2x80x9d and xe2x80x9cxcex2xe2x80x9d may also depend upon, to some extent, other system characteristics and optical properties of the medium, including those of chromophores included therein. Parameter xe2x80x9cxcex3xe2x80x9d may be either a proportionality constant (including, e.g., 1.0) or a system parameter which may change its value according to the characteristics of the wave source, wave detector, and/or medium. Parameter xe2x80x9cBxe2x80x9d generally accounts for lengths of optical paths of photons or electromagnetic waves through the medium, and is predominantly determined by the optical properties of the medium. However, an exact value of parameter xe2x80x9cBxe2x80x9d may also depend on the characteristics of the wave source and/or wave detector as well. A typical example of such parameter xe2x80x9cBxe2x80x9d is conventionally known as a path length factor. It is appreciated that the parameter xe2x80x9cBxe2x80x9d may also take the value of 1.0 where the generalized diffusion equation (1) is reduced to the Beer-Lambert equation. To the contrary, parameter xe2x80x9cLxe2x80x9d is generally geometry-dependent and accounts for a linear distance between the wave source and wave detector. Parameter xe2x80x9cxcex4xe2x80x9d may be either a proportionality constant (including, e.g., 1.0) or a system parameter which may be associated with the wave source, wave detector, and/or medium. Parameter xe2x80x9cxcex5ixe2x80x9d accounts for an optical interaction or interference of photons or electromagnetic waves with an i-th chromophore included in the medium. It is appreciated that, depending upon the definition and value of the parameter xe2x80x9cxcex4xe2x80x9d, the parameter xe2x80x9cxcex5ixe2x80x9d may represent an extinction coefficient, an absorption coefficient, and/or a (reduced) scattering coefficient of the medium or the chromophores included therein. Variable xe2x80x9cCixe2x80x9d represents concentration of the i-th chromophore included the medium, and parameter xe2x80x9c"sgr"xe2x80x9d is either a proportionality constant (including, e.g., 0.0) or a parameter which may be associated with the wave source, wave detector, and/or medium. Despite the numerous parameters of the generalized diffusion equation (1) and various modified versions thereof which will be described in greater detail below, the optical systems and methods of the present invention enable direct determination of absolute values of the chromophore concentrations and/or ratios thereof.
In one aspect of the present invention, a method is provided to solve a set of wave equations applied to an optical system having at least one wave source and at least one wave detector. Photons or electromagnetic waves are irradiated by the wave source, transmitted through the physiological medium including at least one chromophore, and detected by the wave detector. The wave equation, e.g., the generalized diffusion equation (1), expresses the intensity of electromagnetic waves detected by the wave detector (i.e., xe2x80x9cIxe2x80x9d) as a function of system variables (e.g., xe2x80x9cIoxe2x80x9d and xe2x80x9cCixe2x80x9d) and system parameters (e.g., xe2x80x9cxcex1,xe2x80x9d xe2x80x9cxcex2,xe2x80x9d xe2x80x9cxcex3,xe2x80x9d xe2x80x9cB,xe2x80x9d xe2x80x9cL,xe2x80x9d xe2x80x9cxcex4,xe2x80x9d xe2x80x9cxcex5i,xe2x80x9d and xe2x80x9c"sgr"xe2x80x9d). The method generally includes the steps of obtaining multiple sets of equations by applying the wave equation to the optical system capable of irradiating multiple sets of electromagnetic waves having different wave characteristics, eliminating the source-dependent parameters (e.g., xe2x80x9cxcex1xe2x80x9d) and detector-dependent parameter (e.g., xe2x80x9cxcex2xe2x80x9d) therefrom to obtain a set of intermediate equations, providing at least one correlation of the medium-dependent and geometry-dependent parameters (e.g., xe2x80x9cBxe2x80x9d and xe2x80x9cL,xe2x80x9d respectively) with the chromophore concentrations (and/or their ratios), incorporating the correlation into the set of intermediate equations, and obtaining absolute values of the concentrations of the chromophores (and/or ratios thereof) based on the intensities of electromagnetic waves (e.g., xe2x80x9cIxe2x80x9d and xe2x80x9cIoxe2x80x9d) and the medium- or chromophore-dependent parameters (e.g., xe2x80x9cxcex5ixe2x80x9d).
This embodiment of the present invention offers several benefits over the prior art. Contrary to the prior art CWS technology capable of measuring only the changes in the chromophore concentrations, the foregoing method of the present invention provides a direct means for assessing the xe2x80x9cabsolute valuesxe2x80x9d of the chromophore concentrations as well as their ratios in various physiological media, e.g., tissues or cells in internal organs, muscles, and/or body fluids. The foregoing method of the present invention also allows physicians to make direct diagnosis of an xe2x80x9cabsolute propertyxe2x80x9d of the physiological medium (i.e., compared with differential or relative values of the physiological properties obtainable by the prior art CWS technology). Furthermore, as will be described in detail below, the foregoing method of the present invention can be readily incorporated into conventional optical probes including any number of wave sources and detectors arranged in any arbitrary configurations. Therefore, the foregoing method allows construction of optical systems customized to specific clinical applications without compromising their performance characteristics.
Embodiments of this aspect of the present invention may include one or more of the following features.
The generalized diffusion equation (1) may be applied to an optical system with at least one wave source and at least one wave detector:                               I                      m            ⁢                          xe2x80x83                        ⁢            n                          =                              α            m                    ·                      β            n                    ·          γ          ·                      I                          0              ,              m                                ·                      ⅇ                          {                                                                    -                                          B                      mn                                                        ·                                      L                    mn                                    ·                  δ                  ·                                                            ∑                      i                                        ⁢                                          (                                                                        ϵ                          i                                                ⁢                                                  C                          i                                                                    )                                                                      +                σ                            }                                                          (        2        )            
where the subscripts xe2x80x9cmxe2x80x9d and xe2x80x9cnxe2x80x9d represent an m-th wave source and an n-th wave detector, respectively.
The method may include the steps of applying equation (2) to the optical system to obtain a first and a second set of equations, eliminating at least one of xcex1m, xcex2n, xcex3, xcex4, and "sgr" from the first and second set of equations by performing mathematical operations thereon to obtain a third set of equations, providing at least one correlation which correlates the concentrations of the chromophores (or ratios thereof) with one or more terms of the third set of equations including Bmn and/or Lmn, incorporating the above correlation into the third set of equations to replace such terms thereby, and obtaining an expression for absolute values of the concentrations of the chromophores (and/or ratios thereof) based on known or measured values of Imn, Io,m, and xcex5i.
The foregoing method may also include the steps of applying the optical system to the physiological medium including cells of organs, tissues, and body fluids, and measuring the absolute values of the chromophore concentrations (and/or their ratios) based on known or measured values of Imn, Io,m, and xcex5i. The measuring step may include an additional step of monitoring concentrations of oxy- or deoxy-hemoglobin, and/or a ratio thereof such as, e.g., (tissue) oxygen saturation.
The foregoing method may also include the step of determining presence of tumor cells in a finite area of the medium or determining a presence of an ischemic condition as well. In the alternative, the foregoing method may also include the steps of applying the optical system to the physiological medium including transplanted cells of organs and/or tissues and measuring absolute values of the chromophore concentrations (or their ratios) based on known or measured values of Imn, Io,m, and xcex5i. For example, the method may be applied to determine presence of an ischemic condition in the transplanted organs and tissues during or after surgical procedures.
The applying step of the foregoing method may include the step of irradiating the first and second set of electromagnetic waves having different wavelengths, phase angles, amplitudes, harmonics, and/or a combination thereof. For example, in the irradiating step, the first set of electromagnetic waves may have a first wavelength while the second set of electromagnetic waves may have a second wavelength which is different from the first wavelength.
The eliminating step of the foregoing method may include the step of deriving at least one first ratio of two wave equations both of which are selected from one of the first and second sets of the equations. The wave equations may be applied to the same wave source but to different wave detectors, thereby eliminating xcex1n, xcex3, and "sgr" from the first ratio. Alternatively, the wave equations may be applied to two different wave sources but to the same wave detector, thereby eliminating xcex2n, xcex3, and "sgr" from the first ratio. The eliminating step may also include the step of deriving at least one second ratio of two wave equations both of which are selected from the other of the first and second sets of the equations. A sum of or a difference between the first and second ratios may also be obtained so as to eliminate at least one of xcex1m and xcex2n. In the alternative, the eliminating step may include the step of approximating both parameters xe2x80x9cxcex3xe2x80x9d and xe2x80x9cxcex4xe2x80x9d as a unity.
The providing step of the foregoing method may include the step of providing a formula of the medium-dependent and geometry-dependent parameters as a polynomial, sinusoid or other functions of the chromophore concentrations (and/or ratios thereof). Such a formula may also include a zero-th order term. Alternatively, the medium-dependent and geometry-dependent parameters may be approximated as a constant.
In another aspect of the invention, an optical system is provided to determine the absolute values of the concentrations of chromophores in the physiological medium and/or ratios thereof. The optical system may include a body, a source module, a detector module, and a processing module. The source module is supported by the body and is arranged to optically couple with the medium so as to irradiate into the medium two or more sets of electromagnetic waves having different wave characteristics. The detector module is also supported by the body, and is arranged to optically couple with the medium and to detect electromagnetic waves transmitted through the medium. The processing module is also arranged to operatively couple with the detector module and configured to solve a set of wave equations such as equation (1) so that the absolute values of the concentrations of the chromophores (and/or their ratios) can be directly determined. The processing module may be designed to operate at a TRS, PMS or CWS mode.
This embodiment of the present invention offers several benefits over the prior art near-infrared spectroscopy technologies such as TRS, PMS, and CWS. Compared with conventional TRS and PMS technologies, TRS and/or PMS optical systems of the present invention can be provided with better accuracy at a lower cost. Furthermore, the optical systems of the present invention operating at a CWS mode can measure the absolute values of the chromophore concentrations as well as their ratios, e.g., (tissue) oxygen saturation. Accordingly, various optical systems of the present invention can be manufactured as a low-cost and high-resolution hand-held device, bed-side monitoring device, and/or a portable device wearable by patients.
Embodiments of this aspect of the present invention may include one or more of the following features.
The wave source may be arranged to irradiate electromagnetic waves having different wavelengths, phase angles, amplitudes, harmonics or their combination. For example, the first set of the electromagnetic waves may have a first wavelength and a second set of said electromagnetic waves may have a second wavelength which is different from the first wavelength. Alternatively, the first set of electromagnetic waves may be carried by a first carrier wave and the second set of electromagnetic waves may be carried by a second carrier wave which has wave characteristics different from those of the first carrier wave, e.g., different wavelengths, phase angles, amplitudes, harmonics, and their combination.
The processing module may include an algorithm for determining the absolute values of the chromophore concentrations (or their ratios) based on various variables and/or parameters, e.g., the intensity of electromagnetic waves irradiated by the source module, intensity of electromagnetic waves detected by the detector module, and one or more system parameters accounting for interaction or interference of photons or electromagnetic waves with the medium.
The wave equations may include at least one term which is substantially dependent on the optical properties of the medium (i.e., medium-dependent) and/or configuration of the source and detector modules (i.e., geometry-dependent). Examples of such term may include, but not limited to xe2x80x9cBxe2x80x9d and xe2x80x9cLxe2x80x9d of equation (1) or xe2x80x9cBmnxe2x80x9d and xe2x80x9cLmnxe2x80x9d of equation (2). The algorithm of the processing module may include at least one correlation expressing a first function of the term as a second function of the chromophore concentrations (and/or ratios thereof). The second function may be any analytic function, e.g., a polynomial of the concentrations and/or ratios thereof. Alternatively, the algorithm may also be arranged to approximate the second function as a constant.
The source module may include at least one wave source and the detector module at least two wave detectors. Alternatively, the source module may include at least two wave sources while the detector module may include at least one wave detector. It is preferred, however, that both of the source and detector modules include, respectively, at least two wave sources and at least two wave detectors.
In one aspect of medical application of the present invention, the foregoing optical systems and methods therefor may be used to measure the absolute values of concentrations of oxygenated and deoxygenated hemoglobin and/or their ratio. Such optical systems will be beneficial in non-invasively diagnosing ischemic conditions and/or locating ischemia in various organs and tissues. For example, the optical system may be used to prognose or diagnose stroke, cardiac ischemia or other physiological abnormalities originating from or characterized by abnormally low concentration of oxy-hemoglobin. Accordingly, presence of cancerous tumors may be easily detected. The optical systems of the present invention may further be applied to cells disposed in epidermis, corium, and organs such as a lung, liver, and kidney.
In another aspect of medical application of the present invention, the foregoing optical systems and methods therefor may be applied to measure absolute values of the concentrations of oxy- as well as deoxy-hemoglobins to diagnose vascular occlusion during or after various surgical procedures including organ transplantation. In general, prognosis of organ transplantation depends on adequate supply of oxygenated blood to transplanted organs during and post surgical procedure. The optical system of the present invention may be used to detect vascular occlusion in transplanted heart, lung, liver, and kidney in its earliest stage.
In yet another aspect of medical application of the present invention, the foregoing optical systems and methods therefor may be applied to assess various absolute properties of the physiological medium. Examples of such conditions may include, but not limited to, concentrations (or their ratios) of lipids, cytochromes, water, and/or other chromophores in the medium.
The foregoing apparatus and methods of the invention may be employed for various applications, e.g., non-invasively disposed on the medium or, alternatively, to be invasively disposed on an internal medium. As used herein, the xe2x80x9cchromophoresxe2x80x9d may mean any substances in a medium which exhibit at least minimum interaction with photons and/or electromagnetic waves transmitting or propagating therethrough. Examples of such chromophores may include, but not limited to, hemoglobins (e.g., deoxygenated or deoxy-hemoglobin (Hb) and oxygenated or oxy-hemoglobin (HbO)), cytochromes, lipids, water, enzymes, hormones, transmitters, proteins, cholesterols, apoproteins, carbohydrates, cytosomes, blood cells, cytosols, and other optically interacting materials present in the animal or human cells.
The terms xe2x80x9celectromagnetic wavesxe2x80x9d include acoustic or sound waves, near-infrared rays, infrared rays, visible lights, ultraviolet rays, lasers, and/or rays of photons. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood and/or used by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be applied and/or used in the practice of or testing the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.